ONCAlert | Upfront Therapy for mRCC

Maintenance Ixazomib Slows Progression in Myeloma

Tony Berberabe, MPH, and Danielle Ternyila
Published Online: Mar 12,2019
Gareth Morgan, MD, PhD
Gareth Morgan, MD, PhD
Maintenance therapy for 2 years with the oral proteasome inhibitor (PI) ixazomib (Ninlaro) following autologous stem cell transplantation (ASCT) improved progression-free survival (PFS) in patients with multiple myeloma, according to a final analysis from the phase III TOURMALINE-MM3 trial presented at the 2019 Transplantation and Cellular Therapy Meetings.

Gareth Morgan, MD, PhD, the director of myeloma research at NYU Langone Perlmutter Cancer Center, presented the findings, which demonstrated a 28% reduction in the risk of progression and death in patients with newly diagnosed multiple myeloma. The median PFS was 26.5 months with ixazomib compared with 21.3 months with placebo (HR, 0.72; 95% CI, 0.582- 0.890; P = .002).

At a median follow-up of 31 months, the investigators were encouraged because many patients remained on treatment for the duration of the study, with few patients discontinuing ixazomib due to toxicities. These data support the idea that 2-year maintenance can influence disease progression after ASCT. “We designed a double-blind, placebo-controlled trial [that demonstrated] a significant improvement in PFS, and that improvement in survival was achieved at very negligible toxicity,” Morgan said.

In the study, 656 patients were randomized to receive ixazomib (n = 395) or matched placebo (n = 261) on days 1, 8, and 15 of 28-day cycles for up to 2 years or until progressive disease or unacceptable toxicity. Randomization was stratified by induction regimen, preinduction disease stage, and response post transplantation.

Depth of response improved during maintenance therapy in 139 (46%) of 302 patients in the ixazomib group and 60 (32%) of 187 patients in the placebo group, with partial response or very good partial response achieved post transplantation (TABLE).

The investigators reported that 7% of patients in the ixazomib arm and 5% in the placebo arm discontinued treatment due to adverse events (AEs). Forty-two percent of patients taking ixazomib and 26% of patients who received placebo exhibited grade ≥3 AEs. In addition, 27% of patients in the ixazomib arm and 20% in the placebo arm exhibited serious AEs.

Common grade ≥3 AEs were infections (15% vs 8%), including pneumonia (6% vs 4%), gastrointestinal disorders (6% vs 1%), neutropenia (5% vs 3%), and thrombocytopenia (5% vs <1%). Peripheral neuropathy rates were 19% versus 15% (grade 3, <1% vs 0%).

Exploring the use of maintenance therapy for the treatment of patients with cancer was an interesting concept, according to Morgan: “At one stage, people thought that it would not work, but data [involving] immunomodulatory drugs suggested that you could influence PFS and overall survival [OS].” Importantly, maintenance therapy did not affect patients’ quality of life, Morgan said, with no difference observed between the 2 arms.

The role of maintenance therapy has been reviewed extensively as a strategy to prolong the duration of disease control and survival post ASCT in patients with newly diagnosed multiple myeloma. Historically, studies involving interferon alfa and corticosteroids were explored in this setting; however, outcomes were met with high discontinuation rates and significant toxicity.

Prior to this study, maintenance with thalidomide had been shown to improve PFS post ASCT in both phase III studies and meta-analyses; however, poorer outcomes in patients with high-risk cytogenetics have been observed. The poor tolerability profile of thalidomide (Thalomid) also limits its possible treatment duration, with discontinuation rates of up to 84% reported.



Currently, lenalidomide (Revlimid) is the only agent approved for post transplant maintenance, gaining the indication in February 2017. At the time of the study design, however, from early 2014 throughout the enrollment period from July 2014 to March 2016, lenalidomide was not approved for maintenance therapy. Further, there was no standard of care in this setting.

The investigators noted that although the approval for lenalidomide is significant, the agent is associated with second primary malignancies, and its benefit is inconsistent in patients with high-risk characteristics such as cytogenetic abnormalities and renal failure.

“We can safely say now that you can treat people for a prolonged period with an oral PI, ixazomib, that it is well tolerated, and that all subgroups of patients benefit with a significant improvement in PFS,” Morgan said. “We have to wait to see if that translates to an improvement in OS because the patients are doing so well.”
 
 
Reference:
Morgan G, Dimopoulos M, Gay F, et al. Maintenance therapy with the oral proteasome inhibitor (PI) ixazomib significantly prolongs progression-free survival (PFS) following autologous stem cell transplantation (ASCT) in patients with newly diagnosed multiple myeloma (NDMM): phase 3 Tourmaline-MM3 trial. Presented at: 2019 Transplantation and Cellular Therapy Meetings; February 20-24, 2019; Houston, TX. Abstract 23. tct.confex.com/tct/2019/meetingapp. cgi/Paper/13046.



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Maintenance Ixazomib Slows Progression in Myeloma
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